A Master Protocol Empowering Mechanobiology Translation Research in Breast Cancer

METAMECH has been designed to streamline the study of the co-evolutionary landscape between tumor and host cells in a cohort of breast cancer (BC) patients, with the aim of understanding how their outcomes can be significantly improved (e.g. reduction of their chance of recurrence and survival improve). This clinical resource for integrative clinical data and sample collection will allow to generate hypotheses on mechanisms supporting the outgrowth of human metastases, mine for new potentially actionable targets and the selection of appropriate patients for experimentally-driven trials. To achieve the required level of 'experimental precision', patients will enter METAMECH at two different 'therapeutic checkpoints': i) prior to a tumor sampling event (surgery, biopsy) or ii) prior to any line of treatment.

To optimize the enrollment of patients, the longitudinal collection of data/samples and their logistic management, METAMECH has been designed as a flexible infrastructure organized in Tiers for the stepwise comprehension of the biological processes that drive tumor evolution, and precisely:

• TIER0, Retrieving: the ability to retrospectively retrieve clinically annotated BC archival samples to validate/discover new mechanotransduction-linked biomarkers;

• TIER1, Recording: the ability to prospectively record BC characteristics under standard of care treatments and to define new mechanotransduction-linked biomarkers;

• TIER2, Modelling: the ability to develop pertinent experimental models to study the aberrant mechanisms underlying the metastatic outgrowth and define mechanotransduction-targeting therapeutic strategies;

• TIER3, Linking: the ability to access data and samples of patients enrolled in POC trials to prove the efficacy and study/understand resistance mechanisms of mechanotransduction-targeting therapies.